To date, prostate cancer patients originally respond to the androgen ablation therapy but eventually succumb to disease. Collectively, the proposed explanations such as mutations of AR, the change of the steroid specificity of AR through AR mutations, or through AR interaction with coregulators, have been actively investigated. Furthermore, the induction of AR transactivation through the phosphorylation signal cascade may provide an alternative explanation of why the activation of AR is less dependent on androgens. Recently, the P.I. identified the HER2/Neu-MAP kinase-AR pathway. The growth of prostate cancer LNCaP cell could be increased through overexpression and activation of HER2/Neu. The P.I. has also found that the MAP kinase signal cascade could be the factor to active AR and the expression of prostate specific antigen (PSA) in the absence or in the presence of therapeutic concentrations of androgen. In the same report, the P.I. also delineated codon 514 on AR as the MAP kinase target site. The mutation of this MAP kinase site on AR reduced the AR transcriptional activity inside the cell. These results highlight the importance of MAP kinase on the in vivo AR transactivation. The AR is a transcription factor that belongs to the steroid receptor (SR) super-family. Recently, it has been reported that specific sets of proteins were recruited by the SRs as coregulators that may function as bridge factors between the receptors and general transcription factors in the preinitiation complex. Identifying and understanding the function of individual components of these complexes is crucial in determining how SRs regulate their target genes. Results from these studies suggested coactivators not only can enhance AR transcriptional activity, but may also be able to modulate the specificity of sex hormones or antiandrogens on AR-mediated transactivation in prostate cells. Our recent results have provided evidence to link MAP kinase signal to the AR function. It will be of great interest to know if the phosphorylation signal cascade can cross talk to the ARAs and consequently affect the ARA-AR mediated functions in prostate cancer. Therefore, we propose to study the following aims: Aim 1: Identification of in vivo phosphorylation sites in AR and demonstration of their linkage to the HER2/NeuIMAPK-induced AR transactivation. Aim 2: Investigating that phosphorylated AR (by HER2/Neu/MAPK) has a higher capacity to interact with ARAB. Aim 3: Demonstration that phosphorylated ARAs by HER2/Neu/MAPK have higher capacities to interact with AR. Aim 4: Staining of phosphorylated AR and ARAs in different stages of prostate cancer. The accomplishment of this study would provide valuable information of that how MAP kinase signal cross talk to AR and AR associated proteins in molecular mechanism and the pathogenesis of prostate cancer.